Program DRGFIT will be improved by introducing a new and proven minimizing routine which utilizes the method of steepest descent to find a global minimum of a response surface of the six drug-metabolism parameter. The autoradiographic data (labeling index and mitotic rate) which resulted from experiments with 11 different drugs, and which are now being collected and reduced, will be applied to this model in order to obtain the optimized drug metabolism parameters, as functions of drug dosage, for each tissue (large bowel, small bowel, B-16 melanoma, and esophagus). The Monte Carlo program SIVIT will be completed and implemented in order to predict the degree of cell synchrony to be expected from various treatment regimens on the bases of cell kinetic data (OPLM) and dose-response data (DRGFIT). Several treatments will then be explored by computer, and a few experiments will be conducted to test those treatments which are predicted to produce the greatest degree of cell synchrony. Cell kinetic data acquisition which is currently being made by autoradiography, will be conducted in parallel with data acquisition from the on-line Cytofluorgraf and from the FACS. We will attempt by use of biochemical techniques and the cell sorter, to also obtain suspensions of viable crypt cells from the large intestine. Our recently implemented FMF technique will allow us to obtain objective assignment of living cells, from the crypts of the large and small bowels and the B-16 melanoma, with high speed and accuracy, to various phases of the cell cycle (including the non-cycling compartment), before and during treatment. The enzyme-kinetic model DNAMET is being continuously updated in accordance with new pharmaco-enzyme interaction data available from various laboratories. In order to explore the possibility of enhancing drug effects in combination, we will simulate isobols computed for the simultaneous administration of three antimetabolites. BIBLIOGRAPHIC REFERENCES: C. Nicolini and R. Baserga: Cell Synchrony of Lining Epithilium in Mice. II International symposium of Pulse-Cytophotometry, Ed. Schuman J., W. Gohde and T. H. Buchner (1976) European Press. C. Nicolini: The Principle and Methods of Cell Synchronization and Cancer Chemotherapy. Biophysica Et Biochemica Acta Review on Cancer, July, (1976).